Whether or not the brain can use supplemental choline to enhance the synthesis of acetylcholine (ACh) is an important consideration for assessing the merits of using choline or phosphatidylcholine (lecithin) for the treatment of neuropsychiatric disorders postulated to involve hypocholinergic activity. While it is well documented that administered choline is incorporated into ACh, the ability of supplemental choline to increase the synthesis and release of ACh has been questionable. Studies in my laboratory have demonstrated that acute or chronic choline supplementation does not, by itself, enhance the levels of ACh in brain under normal biochemical and physiological conditions. However, supplemental choline prevents the depletion of ACh in brain induced by numerous pharmacological agents that increase the firing of cholinergic neurons. Since the levels of free choline in brains from supplemented rats were not different from controls prior to drug challenge, evidence suggested that the observed effects of choline were mediated by alterations in the mobilization of choline from choline-containing compounds. Studies investigating the release of choline from brain indicated that more choline was released per unit time in tissues from choline-supplemented rats than from controls. In addition, brain tissue from choline-supplemented rats had increased concentrations of total lipid phosphorus as compared with controls. Hence, although choline supplementation does not alter the levels of ACh in brain under normal conditions, it does appear to support ACh synthesis during drug-induced increases in neuronal activity, an effect most likely mediated by alterations in the metabolism of choline-containing phospholipids.